WO 97/38991, published Oct. 23, 1997 (Janssen Pharmaceutica N.V.) discloses substituted tetracyclic tetrahydrofuran derivatives that may be used as therapeutic agents in the treatment or prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders. In particular, the compounds show affinity for the serotonin 5-HT2 receptors, particularly for the 5-HT2A and 5-HT2C-receptors. A number of compounds with a cyclic amine side chain were disclosed which are excluded from this application by way of a disclaimer. The same compounds were also disclosed in Cid J. et al. Bioorganic & Medicinal Chemistry Letters, 14 (2004) 2765-2771.
WO 99/19317, published Apr. 22, 1999 (Janssen Pharmaceutica N.V.) discloses substituted tetracyclic tetrahydrofuran derivatives with a specific halogen substitution pattern on the dibenzoazepine, dibenzooxepine, dibenzothiepine or dibenzosuberane ring. The compounds are useful in the treatment or prevention of CNS disorders, cardiovascular disorders or gastrointestinal disorders and show a faster onset of action over the compounds as disclosed in WO 97/38991. Also, a test was reported (ATN test) on the dopamine antagonizing properties of a number of compounds with a linear amine side chain (by preventing the symptoms elicited with the dopamine agonist apomorphine, such as, for example, agitation and stereotypy), where it was shown that the specific halogen substitution contributed positively to the dopamine antagonism. Such effect was not demonstrated nor suggested for compounds containing a cyclic amine side chain. A number of compounds with a cyclic amine side chain were disclosed which are excluded from this application by way of a disclaimer.
Both WO 03/048146, published Jun. 12, 2003 (Janssen Pharmaceutica N.V.) and WO 03/048147, published Jun. 12, 2003 (Janssen Pharmaceutica N.V.) disclose processes for the preparation of each of the four diastereomers of trans-, respectively cis-fused 3,3a,8,12b-tetrahydro-2H-dibenzo[3,4:6,7]cyclohepta[1,2-b]furan derivatives in a stereochemically pure form from a single enantiomerically pure precursor. The compounds of WO 03/048146 show affinity for 5-HT2 receptors, particularly for 5-HT2A and 5-HT2C receptors. The compounds of WO 03/048147 show affinity for the serotonin 5-HT2A, 5-HT2C and 5-HT7 receptors, the H1-receptors (pIC50=7.15-7.89), D2 and/or D3 receptors and for the norepinephrine reuptake transporters (pIC50=6.03-7.34). The compounds disclosed in the latter two publications do not contain a cyclic amine side chain.
WO 03/040122, published May 15, 2003 (Janssen Pharmaceutica N.V.) discloses mandelate salts of the compounds according to WO 97/38991 and WO 99/19317. Said salts were surprisingly found to be more stable at enhanced temperature and relative humidity than the compounds disclosed in WO 97/38991 and WO 99/19317.